Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries.
Queen Victoria, through two of her five daughters (Princess Alice of the United Kingdom and Princess Beatrice of the United Kingdom), passed the mutation to various royal houses across the continent, including the royal families of Spain, Germany and Russia.
Queen Victoria had no ancestors with the condition but soon after the birth of her eighth child, Leopold, in 1853 it became evident that he had haemophilia (the son Leopold died at the age of 31, from a intra cerebral haemorrhage and was described as "very delicate").
With the appearance of hemophilia in the royal family the Queen could only protest that the disease did not originate in her side of the family.and they often blamed the "curse of the Coburgs". (Potts,1999)
The sixteenth president of United States of America was a Hemophilic.He reigned as the first President of the United States for close to four years. Despite his delicate condition he successfully led his country through its greatest internal crisis, the American civil war.
Get your grade
or your money back
using our Essay Writing Service!
He is remembered for his great leadership during the civil war of 1980's and for his emancipation proclamation that led to freeing of confederate slaves.
Is Haemophila fatal? Does person suffering from Haemophilia suffer from a hamper disease to lead a normal life?
What is Haemophilia
The word haemophilia has as origin two Greek words: haima = blood and philia = affection. In Arabic language; haemophilia means Naaor (Ù†Ø§Ø¹ÙˆØ± ) which means the unstopped bleeding vessel.
Hemophilia is one of the oldest described genetic diseases.An inherited bleeding disorder in males was recognized in Talmudic records of the second century.
The blood of haemophilia patient does not clot normally. ( Handin et al.,2003)
They account for 90-95% of severe congenital coagulation deficiencies. He bleeds for a longer time than normal persons but he does not bleed more profusely or more quickly.
Bleeding may occur anywhere in the body : (Zaiden & Ozturk 2009)
Superficial bleeding such as those cause by abrasions, or shallow lacerations may be prolonged and the scab may easily be broken up due to the lack of fibrin, which may cause re-bleeding. External wounds are usually not serious.
Far more important is internal bleeding (hemorrhaging).
These hemorrhages occur in joints ( especially knees), ankles and elbows; and into tissues and muscles.
When bleeding occurs in a vital organ, specially the brain, a hemophiliac's life is in danger.
Who discovered Haemophilia?
In the whole history of hemophilia, it's generally accepted that the main development in understanding the cause and the inheritance type of the disease accomplished in the last century. But, who really was the first to describe the disease?
We found that the Arabian physician Albucasis may be the first who described the disease. He defined the disease, witnessed some cases, named it, and even suggested a treatment. Then, more than seven centuries had passed until the concern about the disease revived, thanks to its spread in the royal families of Europe.
Albucasis, the First Physician Who Described Hemophilia:
The famous physician Al-Zahrawi - Albucasis (936-1013 AD), in the second Essay of his medical encyclopedia "Kitab al-Tasrif", described a disease which he named " Ø¹Ù„Ø© Ø§Ù„Ø¯Ù… " or blood disease. (Al Zahrawi,1986)
His description corresponds with haemophilia. He was far ahead in his description for many reasons:
Firstly, his naming was indicative of the real cause of the disease.
Secondly, he noticed the spread of the illness in just one village, which is attributed to the inherited nature of it.
Thirdly, he was the first who noticed and described the disease, because, as he said, he didn't read of it in any of the ancient's medical books.
Fourthly, he noticed the limitation of the disease to males and their boys.
Fifthly, he characterized the disease with easy bleeding after minor traumas which is nowadays considered the primal symptom of the disease. He mentioned examples of three boys bled until they died.
Sixthly, he admitted that he didn't know the cause of the disease which was impossible to be discovered in his time. Albucasis didn't pretend that he knew the cause which indicates his scientific method.
Always on Time
Marked to Standard
Finally, he recommended using the cauterization of the bleeding place until the vessels stop bleeding. The treatment he suggested represents the most beneficial remedy available in his time. (Al Zahrawi, 2004)
Who is affected?
Hemophilia may affect people of all races, colours and ethnic origins.
The most severe forms of hemophilia affect almost males only.
Females can be seriously affected only if the father is a hemophiliac and the mother is a carrier, or in the case of X-inactivation when a woman's normal X-chromosome is inactive in the production of factor VIII or IX. These cases are extremely rare.
Parent Xh+Y x XXh+
Gametes Xh+ , Y x X , Xh+
Generation Xh+Xh+, Xh+X , XY, Xh+Y
Status Hemophilic Carrier Normal Hemophilic
Female Female Male Male
As hemophilia is an hereditary disorder, people are affected at birth. This means that children can have hemophilia. In fact, hemophilia is often diagnosed in the first year of life.
Haemophilia A is sometimes called "Royal Haemophilia"because it occurred in the descendants of Queen Victoria while Haemophilia B is sometimes called Christmas disease after Stephen Christmas, the first patient described with this disease. In addition, the first report of its identification was published in the Christmas edition of the British Medical Journal.
Haemophilias are X-linked, recessive, hereditary bleeding disorders, and are caused by a deficiency in clotting factor VIII (haemophilia A) or in clotting factor IX (haemophilia B). ( Bowen DJ,2002)
Epidemiologic and clinical aspects
Haemophilia A, that concerns one male birth out of 5000, is more frequent than haemophilia B (about one male birth out of 30 000).
The clinical severity (Agaliotis et al.,2008)
depends on the importance of the deficiency, giving several forms:
Severe haemophilia, with a residual level of activity for the factor VIII or IX less than or equal to 1 percent
Moderate haemophilia, when the residual level is between 2 and 5 percent
Minor forms with a residual level between 6 and 30 percent.
Biochemical and genetic aspects
The gene coding for clotting factor VIII (F8) is one of the 'big' genes, covering 186 kilobases of the long arm of the X chromosome (position Xq28).
It has 26 exons coding for a protein having 2351 amino acids. The release of the signal peptide allows the secretion of a still inactive protein, made up
of three types of domains A,B and C, more or less repeated.
In the bloodstream,it forms a complex with the von Willebrand factor (FvW). Activation by thrombin leads to the complex dissociating, and starts a cascade of protein cleavages, the produced fragments associating through calcium ions to form the activated factorVIII.
The gene for clotting factor IX (F9) is of medium size (33 kilobases), located at position Xq27 and contains eight exons. The mRNA is translated into a pro-peptide containing six different functional domains.
The cleavage of the signal peptide, and then of the following 18 amino acids, generates a mature protein of 415 amino acids.Activation is the result of the excision of a central peptide, generating a light chain and a heavy chain that stay linked through a disulphide bond.
The activated factors VIII and IX allow the activation of factor X and, therefore, have a central role in the intrinsic coagulation pathway.
A mutational mechanism accounts for about 45 percent of the severe cases of haemophilia A.
It is an inversion of one segment of the X chromosome containing exons 1 to 22 of the F8 gene.
The existence of homologous sequences between intron 22 of the gene and a telomeric region (grey boxes) favours a pathologic intrachromosomal pairing during meiosis.
The recombination between intron 22 and one of the telomeric sequences leads to the inversion of a part of the X chromosome, not detectable through cytogenetics, which interrupts the F8 gene.
This gene can be expressed as a truncated protein corresponding to exons 1 to 22 (from Lakich et al., 1993)
Figure 2.15 Inversion mechanisms in the F8 gene
This inversion is the result of an intrachromosomal recombination between these two homologous sequences, one located in intron 22 and the other one downstream of the gene, towards the telomere of the long arm of chromosome X, and seems to happen essentially during male meiosis.
This Essay is
a Student's Work
This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.Examples of our work
The existence, upstream of the gene, of several copies homologous to the one in intron 22, is responsible for several types of inversion.
In all cases, the result is an interruption of the gene that cannot be transcribed entirely.
Many point mutations have been described, scattered all over the coding sequence.
They consist of 'private' mutations, meaning that they are different in each family
because there is no recurrent mutational mechanism.
These mutations account for about 50 per cent of the severe cases of haemophilia A and almost all of the moderate or minor cases.
They can be nonsense mutations (stop codon) responsible for severe forms, missense mutations with a variable severity, and mutations causing splicing defects, also associated with severe, moderate or minor forms.
Deletions/insertions of a few base pairs can also cause haemophilias of variable severity depending on whether or not they cause a frameshift.
The remaining 5 percent of severe haemophilia cases are due to rearrangements,
most of the time large deletions covering different regions of the gene but whose
breakpoints are not determined in most cases.
Most of the mutations (95 percent) are no-sense or missense point mutations, insertions/deletions of a few base pairs.
Several hundred different mutations are reported and are scattered all over the gene.
The remaining 5 percent are due to larger deletions.
Direct sequencing of amplified genomic DNA has been used to investigate the molecular basis of haemophilia B and thus identify specific amino acids that are essential for maintenance of structure or function of factor IX.
Substitution of Cys 336, Asn 120 results in loss of circulating factor IX antigen
deletion of Arg 37 in gross reduction of circulating protein and loss of activity,
substitution of Arg -4, Arg 333, Asp 64 and Pro 55 cause loss of function without marked reduction in protein serum levels.
Frameshift or point mutations resulting in marked loss of coding information are found in patients who develop antibodies to administered factor IX.
An enhanced rate of mutation is evident at two CpG dinucleotides in the factor IX gene, which accounts for approximately 25% of all point mutations causing haemophilia B known to date.
Diagnosis of haemophilias
The main aim of the genetic diagnosis of haemophilias is to identify women who are carriers of haemophilia, meaning the women are heterozygous, who are not affected but are able to transmit the affected allele, and therefore the disease, to their sons.
In theory, when it is a sporadic haemophilia, a third of the cases are due to new mutations. In this case, the purpose of the genetic study is to define with certainty the status of the women requesting, in order to perform eventually an early prenatal diagnosis for the carriers.
Biological diagnosis :
The biological diagnosis relies on the dosage of the clotting activities of the two factors (FVIIIc or FIXc) in haemophiliacs.
The combination with an antigen dosage makes it possible to distinguish between haemophilia where the deficient factor is absent in the bloodstream (levels of clotting factors and antigens decreased) from haemophilia where the factor is present but not functional (the level of clotting factor diminished but antigens normal or slightly diminished).
The dosage of the clotting factors in women for whom the carrier status is being determined is not always informative: because of the lyonization process (random X chromosome inactivation in women) and of the high variability of the normal values of the clotting factors, a third of the carrier women have a normal haemostasis assessment.
The detection of haemophilia B carriers relies on the dosage of FIXc: a dosage reading of FIXc < 0.6 several times in a female relative of a patient with haemophilia B is sufficient to diagnose her as a carrier.
Concerning the detection of haemophilia A, the dosage of factor VIIIc is not sufficient because its level also depends on theFvW (its transporter) level in the bloodstream.
Therefore, it is necessary to measure the FvW antigen and to calculate the fraction FVIIIc/FvWAg.
These readings should not be performed during pregnancy as the synthesis of these factors in the liver increases at this time.
A reading showing the fraction FVIIIc/FvWAg < 0.7 several times in a female relative is sufficient to diagnose her as a carrier.
In general, two types of approach allow the detection of a mutated allele:
Direct approach, based on the identification of the mutations responsible for the disease
Indirect approach relying on the linkage between the disease locus and polymorphic markers located near or inside the gene.
The advantage of the direct analysis is considerable in haemophilia where the status of the women has to be determined.
The identification of a pathogenic mutation in a haemophiliac makes it possible to offer a simple screening of all potential carrier women in the family, even for
those who are only distantly related.
In contrast, the indirect approach often requires a study of a large number of family members and cannot give the status of the mother of a sporadic haemophiliac (the mothers of affected individuals are not necessarily carriers because one case out of three can result from a new mutation).
In case of Haemophilia A:
The direct approach for moderate haemophilia A relies on the search for point
mutations in all coding sequences of the gene.This work is time consuming because
of the size of the gene and the heterogeneity of the mutations, and can only be done
by a few laboratories.
Therefore, an indirect approach is more often used.
The direct approach is more often proposed in severe forms for the search of an
inversion. This is usually performed on the genomic DNA by Southern blot,which
can detect several inversion types.
About 85 percent of the inversions are due to a recombination between a sequence in intron 22 of the F 8 gene and an extragenic homologous copy located distally (type 1 inversion)
12 percent are due to a recombination with a proximal homologous copy (type 2 inversion)
3 percent result from a recombination with an extra copy.
The two most frequent types of inversion are represented in this figure and the corresponding photo.
Hybridization is realized with a probe (probe a) corresponding to the part of intron 22 of the gene F8 whose sequence is also present outside the gene and is responsible for inversions (see Figure 2.15).
The 21.5 kb band corresponds to the intragenic copy (intron 22), the 16 kb band corresponds to the distal extragenic copy and the 14kb one, to the proximal extragenic copy. The 20, 17.5 and 15.5 kb bands correspond to copies rearranged by the inversion.
Figure 2.16 Southern blot to search for an inversion of the F8 gene
More recently, the setting up of a long fragment amplification technique (long PCR) facilitates the search for inversion, but cannot determine the type of inversion involved.
The indirect approach relies on the study of the co-transmission of the pathogenic
mutation with DNA markers. Several types of markers are used.
RFLPs notably a BclI site in intron 18, and an XbaI site in intron 22.
In the latter case, the presence of repeat sequences in intron 22 and upstream of the gene makes the interpretation of the results more complicated.
Microsatellites notably at the level of introns 13 and 22, the most used markers because they are multi-allelic.
(a) According to the data given by the pedigree, I2 and II3 are carriers. The III3 female inherited from her mother II3 the allele 24 that is linked with haemophilia in this family. Therefore she can be considered as a carrier for haemophilia A, assuming there is no recombination (the risk of which is generally considered to be negligible with an intragenic marker). It has to be noted that in the case represented here, a false paternity can lead to a diagnostic error in III3.
(b) This example represents a sporadic case of haemophilia. The female III3 does not have a common allele with the haemophiliac III1 (exclusion diagnosis). However, it is not possible to conclude on the status of II4 because she shares an allele with her haemophiliac nephew.
Figure 2.17 Indirect diagnosis example using intragenic microsatellites analysis
When the intragenic markers do not give any information, it is possible to use
extragenic markers but it is indispensable to take into account the risk of having a
recombination between the marker and the F8gene that can cause an error in the
In the case of haemophilia B,
It is simpler because the smaller size of the gene makes the direct study more accessible as a routine technique, despite the large amount of molecular heterogeneity.
It consists of the use of 'scanning' techniques to test the whole gene for the presence of mutations responsible for the disease in each family.
In the case of a negative result, large deletions can be searched for.
Finally, several intragenic markers allow realization of an indirect diagnosis, in the very few cases where no mutations have been detected using the direct approach.
Prenatal diagnosis always starts with the determination of the sex of the
fetus using the karyotype because, except in a few cases, only boys are affected.
The risk of a woman being a carrier should be precisely calculated, taking into account her position in the pedigree,the result of her haemostasis tests and whether or not she previously has had healthy sons (theory of conditional probability).
Ultimately, when the prenatal diagnosis cannot be performed using molecular
genetics, it can be done by measuring the level of clotting factors in blood from
the umbilical cord, after a sonogram has been performed to determine the sex. The
collection and the dosage are delicate.
The contamination of the cord blood with maternal blood or by amniotic fluid can be at the origin of errors in the diagnosis and requires checking the purity of the fetal collection.
If the mutation is known, then restriction fragment length polymorphism (RFLP) can be performed on chorionic villous or amniocentesis samples.
Inversion of the factor VIII gene can be detected by Southern blot.
If the mutation is not known, gene sequencing can be performed.
A reduced factor VIII C-to-vWF antigen ratio below 0.7 is suggestive of carrier status.
Direct genetic testing for known gene mutation is more accurate.
Direct mutation analysis is available in several laboratories for unknown FVIII or FIX mutations.
Linkage analysis by RFLP in multiple family members can be used.
FIX level is often normal in FIX carriers.
Female carriers are still very difficult to diagnose. Knowing the molecular defects at
the origin of the disease should make this less difficult and allow the determination
of the carrier status of these women to offer an early prenatal diagnosis.
As for all genetic diseases, the direct study of the causative mutation in each family should be preferred when possible.
In contrast, the indirect approach through the study of marker segregation makes it possible to solve most of the cases, but the study of sporadic haemophilia A can sometimes still remain difficult.
The research that reveals the biochemical basis of haemophilia suggested that haemophiliacs could be treated by transfusions with the missing blood-clotting factors.
Begining in the 1960s, the clotting proteins were purified from blood obtained from large number of donors & administered to haemophiliacs in concentrated form. This process was expensive & the concentrated factors often were not available for haemophiliacs in many countries.
During the 1980s, many people with haemophilia developed the Acquired Immune Defficiency Syndrome because they were given clotting factors that had been collected from donated blood.The blood donations had been pooled to obtain the clotting factors in quantity and alas , some of the blood was contaminated with Human ImmunoDefficiency Virus "HIV" causing the AIDS. Most of them died.
Prior to the use of modern blood screening methods and the advent of recombinant Factor VIII, blood born diseases such as hepatitis and HIV were very common in patients with haemophilia as a result of treatment. (Coombes, 2007)
Fortunately, advances in genetic engineering provides SIMPLER , CHEAPER , more RELIABLE & SAFER ways of obtaining crucial clotting factors.
The normal genes that encode factors VIII & IX were isolated from DNA samples & each gene was introduced to cells that could be cultured in the laboratory.
Cell lines capable of synthesizing large amount of the clotting factors were then developed from these cultures to permit the industrial production of each factor.
(Snustad & Simmons,2006)